自噬小体绑定化合物(ATTEC)靶向降解线粒体及其潜在治疗效果  

Targeted clearance of mitochondria by an autophagy-tethering compound(ATTEC)and its potential therapeutic effects

作　　者：谭水霞 王达 付玉华 郑惠文 刘妍 鲁伯埙 Shuixia Tan;Da Wang;Yuhua Fu;Huiwen Zheng;Yan Liu;Boxun Lu(Neurology Department at Huashan Hospital,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Institutes of Brain Science,School of Life Sciences,Fudan University,Shanghai 200438,China;Institute for Stem Cell and Neural Regeneration,School of Pharmacy,State Key Laboratory of Reproductive Medicine,Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing 211166,China)

机构地区：[1]Neurology Department at Huashan Hospital,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Institutes of Brain Science,School of Life Sciences,Fudan University,Shanghai 200438,China [2]Institute for Stem Cell and Neural Regeneration,School of Pharmacy,State Key Laboratory of Reproductive Medicine,Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing 211166,China

出　　处：《Science Bulletin》2023年第23期3013-3026,M0006,共15页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81925012,92049301,and 82050008);the Innovation Program of Shanghai Municipal Education Commission(2021-01-07-00-07.E00074);the New Cornerstone Science Foundation(NCI202242);the Shanghai Municipal Science and Technology(20JC1410900,major project(2018SHZDZX01)and ZJLab);the Science and Technology Commission of Shanghai Municipality(22S11900100);the fellowship of China Postdoctoral Science Foundation(2021M690686)。

摘　　要：功能异常的线粒体的累积会诱发多种神经退化相关疾病,如帕金森氏病(PD)和唐氏综合征(DS).借助小分子化合物促进线粒体的降解被认为可以缓解这类疾病的进程.然而,目前尚缺乏这样一类高效、安全的靶向降解线粒体的小分子化合物.本研究借助一种名为自噬小体绑定化合物(ATTEC)的新型靶向降解技术,创造性地合成一种能同时结合自噬关键分子LC3B以及线粒体外膜蛋白TSPO的小分子化合物—mT1,并发现该化合物能够有效地降解细胞中的线粒体.借助分子生物学及细胞生物学手段,作者证明mT1能够促进LC3B和TSPO结合,从而将线粒体靶向自噬小体,并进一步与溶酶体融合而降解.此外,在PD的细胞模型和DS的类器官模型中证明mT1能够通过促进线粒体的清除而改善相应的病理学表型.该研究将ATTEC技术的应用范畴拓展到亚细胞器的层面,并为以PD和DS为代表的一类线粒体异常引起的疾病提供了一种潜在的新治疗策略.Increased mitochondrial damage plays a critical role in many neurodegeneration-related diseases such as Parkinson’s disease(PD)and Down syndrome(DS).Thus,enhancement of mitochondrial degradation by small molecule compounds may provide promising new strategies to tackle these diseases.Here,we explored the strategy to induce clearance of mitochondria by targeting them to the autophagy machinery by autophagy-tethering compounds(ATTECs).We provided the proof-of-concept evidence demonstrating that the bifunctional compound(mT1)binding to both the outer mitochondrial membrane protein TSPO and the autophagosome protein LC3B simultaneously may enhance the engulfment of damaged mitochondria by autophagosomes and subsequent autophagic degradation of them.In addition,preliminary experiments suggest that mT1 attenuated disease-relevant phenotypes in both a PD cellular model and a DS organoid model.Taken together,we demonstrate the possibility of degrading mitochondria by bifunctional ATTECs,which confirms the capability of degrading organelles by ATTECs and provides potential new strategies in the intervention of mitochondria-related disorders.

关 键 词：Targeted mitochondrial degradation Autophagy-tethering compounds Chimera compound LYSOSOME TSPO Neurodegenerative diseases 

分 类 号：R741.02[医药卫生—神经病学与精神病学]